HIV infection is characterized by an extensive loss of CD4 T cells very early during infection. This coupled with the demonstration that HIV specific CD4 T cell are preferentially infected and destroyed during the course of HIV infection suggests that the ability of the immune system to generate anti-viral immune responses to control HIV is severely compromised very early during HIV infection. Recent studies in small animal modes and HIV infected subjects treated with anti-retroviral therapy (ART) during primary infection indicate that early loss of CD4 T cells may have significant implications for the generation and maintenance of anti-viral CDS T cell responses. The exact role of CD4 T cells in CDS mediated control of HIV infection has not been completely delineated. The long term objectives of this study are to delineate the role of CD4 T cell help in the generation of anti-viral immune responses, and to determine how these responses correlate with durable control of infection and long term outcome. The Specific Aims of this proposal are (1) to determine if early initiation of ART can preserve CD4 T cells in peripheral and mucosal tissues, and if this preservation correlates with qualitative changes in the nature of anti-viral CDS T cell responses (2) to examine if the qualitative differences in the nature of CDS T cell responses correlate with durable viral control and favorable long term outcome after cessation of ART. We hypothesize that early ART will preserve CD4 T cells that in turn will lead to generation of stronger and more effective poly functional CDS T cell responses that will aid in better control of viral infection. Rhesus macaques infected with SIVmac239 and treated with PMPA and FTC will be used in this study. The degree of CD4 T cell preservation in both peripheral and mucosal tissues after ART will be determined using multi-color flow cytometry and molecular techniques. SIV specific CDS T cell responses will be evaluated by measuring multiple functional markers simultaneously using intracellular staining and multi-color flow cytometry. These studies will provide extremely valuable insights into the role of CD4 T cells in CDS mediated control of HIV infection, and will help develop better therapeutic approaches for durable control of HIV infection. [unreadable] [unreadable] [unreadable]